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Abstract:

A feeding regimen for an infant which includes (a) feeding to a newborn
infant a first composition including a fat or lipid; a protein source,
wherein the protein source has from about 72% to about 90% whey and from
about 10% to about 28% casein; a prebiotic composition; and at least
about 72 IU/100 kcal of vitamin D, and (b) feeding to a later stage
infant a second composition which includes a fat or lipid; a protein
source, wherein the protein source has from about 50% to about 70% whey
and from about 30% to about 50% casein; a prebiotic composition; and no
greater than 70 IU/100 kcal of vitamin D.

Claims:

1. A feeding regimen for an infant, comprising (a) feeding to a newborn
infant a first composition which comprises: i. a fat or lipid; ii. a
protein source, wherein the protein source comprises from about 72% to
about 90% whey and from about 10% to about 28% casein; iii. a prebiotic
composition; iv. at least about 72 IU/100 kcal of vitamin D, and (b)
feeding to a later stage infant a second composition which comprises: i.
a fat or lipid; ii. a protein source, wherein the protein source
comprises from about 50% to about 70% whey and from about 30% to about
50% casein; iii. a prebiotic composition; iv. no greater than 70 IU/100
kcal of vitamin D.

2. The feeding regimen of claim 1, wherein the first composition
comprises from about 74 to about 90 IU of vitamin D.

3. The feeding regimen of claim 1, wherein the second composition
comprises from about 52 to about 67 IU of vitamin D.

4. The feeding regimen of claim 1, wherein each of the first and second
compositions comprises about 3 to about 7 g/100 kcal of a fat or lipid.

5. The feeding regimen of claim 1, wherein each of the first and second
compositions comprises about 1 to about 5 g/100 kcal of a protein source.

6. The feeding regimen of claim 1, wherein each of the first and second
compositions comprises about 5 to about 100 mg/100 kcal of a source of
long chain polyunsaturated fatty acids which include DHA.

7. The feeding regimen of claim 1, wherein the prebiotic composition of
each of the first and second compositions comprises at least 20% of an
oligosaccharide which comprises galacto-oligosaccharide.

8. The feeding regimen of claim 7, wherein the prebiotic composition of
each of the first and second compositions comprises about 2.0 g/L to
about 8.0 g/L of a prebiotic composition having at least 20% of an
oligosaccharide which comprises galacto-oligosaccharide.

9. The feeding regimen of claim 1, wherein the prebiotic composition of
each of the first and second compositions further comprises polydextrose.

10. The feeding regimen of claim 1, wherein each of the first and second
compositions further comprises at least one probiotic.

11. The feeding regimen of claim 10, wherein the probiotic is selected
from the group consisting of Bifidobacteria spp., Lactobacillus spp and
combinations thereof.

12. The feeding regimen of claim 1, wherein the first nutritional
composition comprises at least about 3.95 milligrams (mg)/100 kcal of
cholesterol and the second nutritional composition comprises no greater
than about 3.90 mg/100 kcal of cholesterol.

13. A method for providing nutrition to an infant, comprising (a) feeding
to a newborn infant a first composition which comprises: i. a fat or
lipid; ii. a protein source, wherein the protein source comprises from
about 72% to about 90% whey and from about 10% to about 28% casein; iii.
a prebiotic composition; iv. at least about 72 IU/100 kcal of vitamin D,
and (b) feeding to a later stage infant a second composition which
comprises: i. a fat or lipid; ii. a protein source, wherein the protein
source comprises from about 50% to about 70% whey and from about 30% to
about 50% casein; iii. a prebiotic composition; iv. no greater than 70
IU/100 kcal of vitamin D.

14. The method of claim 13, wherein the first composition comprises from
about 74 to about 90 IU of vitamin D.

15. The method of claim 13, wherein the second composition comprises from
about 52 to about 67 IU of vitamin D.

16. The method of claim 13, wherein each of the first and second
compositions comprises about 3 to about 7 g/100 kcal of a fat or lipid.

17. The method of claim 13, wherein each of the first and second
compositions comprises about 1 to about 5 g/100 kcal of a protein source.

18. The method of claim 13, wherein each of the first and second
compositions comprises about 5 to about 100 mg/100 kcal of a source of
long chain polyunsaturated fatty acids which include DHA.

19. The method of claim 13, wherein the prebiotic composition of each of
the first and second compositions comprises at least 20% of an
oligosaccharide which comprises galacto-oligosaccharide.

20. The method of claim 19, wherein the prebiotic composition of each of
the first and second compositions comprises about 2.0 g/L to about 8.0
g/L of a prebiotic composition having at least 20% of an oligosaccharide
which comprises galacto-oligosaccharide.

21. The method of claim 13, wherein the prebiotic composition of each of
the first and second compositions further comprises polydextrose.

22. The method of claim 143 wherein each of the first and second
compositions further comprises at least one probiotic.

23. The method of claim 22, wherein the probiotic is selected from the
group consisting of Bifidobacteria spp., Lactobacillus spp and
combinations thereof.

24. The method of claim 13, wherein the first nutritional composition
comprises at least about 3.95 milligrams (mg)/100 kcal of cholesterol and
the second nutritional composition comprises no greater than about 3.90
mg/100 kcal of cholesterol.

Description:

TECHNICAL FIELD

[0001] This disclosure relates generally to the field of nutritional
feeding regimen for infants. More particularly, the disclosure relates to
a staged nutritional feeding regimen for infants, which provides improved
nutritional functionality, more closely aligned with an infant's needs as
he or she develops. More specifically, it is widely believed that an
infant's nutritional needs differ during early development; indeed, it is
logical that the nutritional needs of a newborn (i.e., a human infant
from birth through 4 months of age) differ from the nutritional needs of
a later stage infant (i.e., from 4 months of age through 1 year).

BACKGROUND

[0002] Certain factors present in human breast milk are believed to be
beneficial to the infant developing body. For instance, a developing
infant has certain requirements relating to fats and proteins, as well as
other nutrients. In addition, the gut microflora of a human is a complex
collection of interrelated microbes which act together to facilitate the
digestive process. In the case of infants, the gut microflora is rapidly
established in the first few weeks following birth, through the first
year of development. Moreover, functional proteins such as transforming
growth factor-beta (TGF-β) play a significant role in many processes
necessary for health and development in infants. However, the needs of an
infant for the foregoing changes during development.

[0003] In the breast-fed infant, for example, Bifidobacterium spp.
dominate among intestinal bacteria, with Streptococcus spp. and
Lactobacillus spp. as less common contributors. In contrast, the
microflora of formula-fed infants is more diverse, containing
Bifidobacterium spp. and Bacteroides spp. as well as the more pathogenic
species, Staphylococcus, Escherichia coli and Clostridia. The varied
species of Bifidobacterium in the stools of breast-fed and formula-fed
infants differ as well.

[0004] Bifidobacteria are generally considered "beneficial" bacteria and
are known to protect against colonization by pathogenic bacteria. This
likely occurs through competition for cell surface receptors, competition
for essential nutrients, production of anti-microbial agents, and
production of inhibitory compounds such as short chain fatty acids (SCFA)
which may decrease fecal pH and inhibit potentially pathogenic bacteria.

[0005] Bifidobacteria are also associated with resistance to
gastrointestinal (GI) tract and respiratory infection as well as an
enhanced immune function, especially in children and infants. Therefore,
the promotion of an intestinal environment in which Bifidobacteria
dominate has become a goal in the development of nutritional
compositions, including nutritional formulations for adults and children
and compositions for formula-fed infants.

[0006] Human milk (HM) contains a number of factors that may contribute to
the growth and population of Bifidobacteria in the gut microflora of
infants. Among these factors is a complex mixture of more than 130
different oligosaccharides that reach levels as high as 8-12 g/L in
transitional and mature milk. Kunz, et al., Oligosaccharides in Human
Milk: Structure, Functional, and Metabolic Aspects, Ann. Rev. Nutr. 20:
699-722 (2000). These oligosaccharides are resistant to enzymatic
digestion in the upper gastrointestinal tract and reach the colon intact,
where they serve as substrates for colonic fermentation.

[0007] HM oligosaccharides are believed to elicit an increase in the
number of Bifidobacteria in the colonic flora, along with a reduction in
the number of potentially pathogenic bacteria. Kunz, et al.,
Oligosaccharides in Human Milk: Structure, Functional, and Metabolic
Aspects, Ann. Rev. Nutr. 20: 699-722 (2000); Newburg, Do the Binding
Properties of Oligosaccharides in Milk Protect Human Infants from
Gastrointestinal Bacteria?, J. Nutr. 217:S980-S984 (1997). One way that
HM oligosaccharides may increase the number of Bifidobacteria and reduce
the number of potentially pathogenic bacteria is by acting as competitive
receptors and inhibiting the binding of pathogens to the cell surface.
Rivero-Urgell, et al., Oligosaccharides: Application in Infant Food,
Early Hum. Dev. 65(S):43-52 (2001).

[0008] In addition to reducing the number of pathogenic bacteria and
promoting the population of Bifidobacteria,when HM oligosaccharides are
fermented, they produce SCFAs such as acetic, propionic and butyric
acids. These SCFAs are believed to contribute to caloric content, serve
as a major energy source for the intestinal epithelium, stimulate sodium
and water absorption in the colon, and enhance small bowel digestion and
absorption. In addition, SCFA are believed to contribute to overall
gastrointestinal health by modulating gastrointestinal development and
immune function.

[0009] The fermentation of HM oligosaccharides also reduces fecal ammonia,
amine, and phenol concentrations, which have been implicated as the major
odorous components of feces. Cummings & Macfarlane, The Control and
Consequences of Bacterial Fermentation in the Human Colon, J. Appl.
Bacteriol. 70:443-459 (1991); Miner & Hazen, Ammonia and Amines:
Components of Swine-Building Odor ASAE 12:772-774 (1969); Spoelstra,
Origin of Objectionable Components in Piggery Wastes and the Possibility
of Applying Indicator Components for Studying Odour Development, Agric.
Environ. 5:241-260 (1980); O'Neill & Phillips, A Review of the Control of
Odor Nuisance from Livestock Buildings: Part 3. Properties of the Odorous
Substances which have been Identified in Livestock Wastes or in the Air
Around them J. Agric. Eng. Res. 53:23-50 (1992).

[0010] As a result of the oligosaccharides present in HM, the SCFA profile
of a breast-fed infant is very different from that of a formula-fed
infant. For example, breast-fed infants produce virtually no butyrate,
with acetate comprising approximately 96% of the total SCFA production.
Lifschitz, et al., Characterization of Carbohydrate Fermentation in Feces
of Formula-Fed and Breast-Fed Infants, Pediatr. Res. 27:165-169 (1990);
Siigur, et al., Faecal Short-Chain Fatty Acids in Breast-Fed and
Bottle-Fed Infants. Acta. Paediatr. 82:536-538 (1993); Edwards, et al.,
Faecal Short-Chain Fatty Acids in Breast-Fed and Formula-Fed Babies,
Acta. Paediatr. 72:459-462 (1994); Parrett & Edwards, In Vitro
Fermentation of Carbohydrates by Breast Fed and Formula Fed Infants,
Arch. Dis. Child 76:249-253 (1997). In contrast, while formula-fed
infants also have acetate (74%) as the major SCFA in feces, they have
considerable amounts of propionate (23%) and small amounts of butyrate
(3%) present as well. These differences between the SCFA profiles of
breast-fed infants and formula-fed infants could affect the energy,
digestion, and overall health of the formula-fed infant.

[0011] Because cow's milk and commercially available infant formulas that
are based on cow's milk provide only trace amounts of oligosaccharides,
prebiotics are often used to supplement the diet of formula-fed infants.
Prebiotics have been defined as "non-digestible food ingredients that
beneficially affect the host by selectively stimulating the growth and/or
activity of one or a limited number of bacteria in the colon that can
improve the health of the host". Gibson, G. R. & Roberfroid, M. B.,
Dietary Modulation of the Human Colonic Microbiota-Introducing the
Concept of Probiotics, J. Nutr. 125:1401-1412 (1995). Common prebiotics
include fructo-oligosaccharide, gluco-oligosaccharide,
galacto-oligosaccharide, isomalto-oligosaccharide, xylo-oligosaccharide
and lactulose.

[0012] In addition, other factors present in human breast milk are
believed to be beneficial to the developing body. For instance, as noted,
functional proteins such as lactoferrin and transforming growth
factor-beta (TGF-β) play a significant role in many processes
necessary for health and development, in infants and children, as well as
adults.

[0013] An infant also has nutritional requirements for other components of
HM. For instance, certain nucleotides, vitamins, and the nutrients are
also necessary or beneficial for the development level of an infant.

[0014] It is appreciated that HM changes during the growth and development
of an infant, "automatically" adjusting to provide what are believed to
be the proper nutrients, at the proper levels, at the proper times during
growth. While a conventional "one size fits all" infant formula can
provide adequate nutrition for a formula-fed infant, such formulas do not
account for the changing requirements during development. In the case of
a formula-fed infant, it would be beneficial to provide an infant feeding
regimen which includes nutritional compositions tailored to provide a
combination of nutrients designed to encourage healthy development and
growth at each stage, at the levels believed most appropriate for the
respective stages. Included in the nutritional compositions should be a
prebiotic substance that simulates the functional attributes of human
milk oligosaccharides in infants, such as an increase in the population
and species of beneficial bacteria in the infant gut and production of a
SCFA profile similar to that of a breast-fed infant. Additionally, the
nutritional composition should be well tolerated in animals, especially
human infants and should not produce or cause excess gas, abdominal
distension, bloating or diarrhea.

BRIEF SUMMARY

[0015] Briefly, the present disclosure is directed, in an embodiment, to
an infant feeding regimen which includes a plurality of different
nutritional compositions, each comprising a lipid or fat, a protein
source, and a prebiotic composition, as well as other nutrients present
at certain specific levels, especially vitamin D. In certain preferred
embodiments, the compositions include a source of long chain
polyunsaturated fatty acids which include docosahexanoic acid (DHA).
Also, in certain embodiments, the prebiotic comprises at least 20% of an
oligosaccharide which comprises galacto-oligosaccharide, such as a
combination of galacto-oligosaccharide and polydextrose.

[0016] In certain embodiments, the feeding regimen of the present
disclosure includes:

[0017] A. A first nutritional composition which comprises: [0018] i. up
to about 7 grams (g)/100 kilocalories (kcal) of a fat or lipid, more
preferably about 3 to about 7 g/100 kcal of a fat or lipid; [0019] ii. up
to about 5 g/100 kcal of a protein source, more preferably about 1 to
about 5 g/100 kcal of a protein source, wherein the protein source
comprises from about 72% to about 90% whey and from about 10% to about
28% casein; [0020] iii. about 1.0 to about 10.0 g/liter (L) of a
prebiotic composition; and [0021] iv. at least about 72 International
Units (IU)/100 kcal of vitamin D, more preferably from about 74 to about
90 IU of vitamin D, and

[0022] B. A second nutritional composition which comprises: [0023] i. up
to about 7 g/100 kcal of a fat or lipid, more preferably about 3 to about
7 g/100 kcal of a fat or lipid; [0024] ii. up to about 5 g/100 kcal of a
protein source, more preferably about 1 to about 5 g/100 kcal of a
protein source, wherein the protein source comprises from about 50% to
about 70% whey and from about 30% to about 50% casein; [0025] iii. about
1.0 to about 10.0 g/L of a prebiotic composition; and [0026] iv. no
greater than 70 IU/100 kcal of vitamin D, more preferably from about 52
to about 67 IU of vitamin D.

[0027] In certain embodiments, the prebiotic composition of the first and
second nutritional composition comprises at least 20% of an
oligosaccharide which comprises galacto-oligosaccharide, more preferably
about 2.0 g/L to about 8.0 g/L of a prebiotic composition having at least
20% of an oligosaccharide which comprises galacto-oligosaccharide;
moreover, each of the first and second nutritional compositions can, in
some embodiments, also comprise about 5 to about 100 mg/100 kcal of a
source of long chain polyunsaturated fatty acids which include DHA, more
preferably about 10 to about 50 mg/100 kcal of a source of long chain
polyunsaturated fatty acids which include DHA.

[0028] In certain embodiments of the present disclosure, the first
nutritional composition also includes at least about 3.95 milligrams
(mg)/100 kcal of cholesterol, more preferably from about 4.00 to about
4.90 mg/100 kcal of cholesterol, and the second nutritional composition
also includes no greater than about 3.90 mg/100 kcal of cholesterol, more
preferably form about 2.60 to about 3.85 mg/100 kcal of cholesterol.

[0029] In the preferred embodiments, the first nutritional composition is
fed to a newborn, whereas the second nutritional composition is fed to a
later stage infant.

DETAILED DESCRIPTION

[0030] The present disclosure provides a feeding regimen which changes
with the developmental stage of an infant, from newborn to later stage
infant (as defined hereinabove). The nutritional products that described
are easily digested, provide physiochemical benefits, and/or provide
physiological benefits, and are tailored to the level of development of
the infant being fed. In an embodiment of the present disclosure, a
plurality of nutritional compositions is provided, including one for a
newborn infant and one for a later stage infant. In certain embodiments,
each nutritional composition comprises a lipid or fat, a protein source,
Vitamin D, a prebiotic composition, especially one having at least 20% of
an oligosaccharide which comprises a mixture of D-glucose and D-galactose
(commonly referred to as galacto-oligosaccharide or
trans-galacto-oligosaccharide, or GOS), and, optionally a source of long
chain polyunsaturated fatty acids which include docosahexanoic acid
(DHA). In some embodiments, the prebiotic comprises a combination of
galacto-oligosaccharide and polydextrose.

[0031] More particularly, in an embodiment, the feeding regimen includes
feeding to a newborn infant a composition which comprises: [0032] i. up
to about 7 g/100 kcal of a fat or lipid, more preferably about 3 to about
7 g/100 kcal of a fat or lipid; [0033] ii. up to about 5 g/100 kcal of a
protein source, more preferably about 1 to about 5 g/100 kcal of a
protein source, wherein the protein source comprises from about 72% to
about 90% whey and from about 10% to about 28% casein; [0034] iii. about
1.0 to about 10.0 g/L of a prebiotic composition; and [0035] iv. at least
about 72 IU/100 kcal of vitamin D, more preferably from about 74 to about
90 IU of vitamin D, and feeding to a later stage infant a composition
which comprises: [0036] i. up to about 7 g/100 kcal of a fat or lipid,
more preferably about 3 to about 7 g/100 kcal of a fat or lipid; [0037]
ii. up to about 5 g/100 kcal of a protein source, more preferably about 1
to about 5 g/100 kcal of a protein source, wherein the protein source
comprises from about 50% to about 70% whey and from about 30% to about
50% casein; [0038] iii. about 1.0 to about 10.0 g/L of a prebiotic
composition; and [0039] iv. no greater than 70 IU/100 kcal of vitamin D,
more preferably from about 52 to about 67 IU of vitamin D.

[0040] In other embodiments, the feeding regimen of the present disclosure
includes:

[0041] A. A first nutritional composition which comprises: [0042] i. up
to about 7 grams (g)/100 kilocalories (kcal) of a fat or lipid, more
preferably about 3 to about 7 g/100 kcal of a fat or lipid; [0043] ii. up
to about 5 g/100 kcal of a protein source, more preferably about 1 to
about 5 g/100 kcal of a protein source, wherein the protein source
comprises from about 72% to about 90% whey and from about 10% to about
28% casein; [0044] iii. about 1.0 to about 10.0 g/liter (L) of a
prebiotic composition [0045] iv. at least about 3.95 milligrams (mg)/100
kcal of cholesterol, more preferably from about 4.00 to about 4.90 mg/100
kcal of cholesterol; and [0046] v. at least about 72 International Units
(IU)/100 kcal of vitamin D, more preferably from about 74 to about 90 IU
of vitamin D, and

[0047] B. A second nutritional composition which comprises: [0048] i. up
to about 7 g/100 kcal of a fat or lipid, more preferably about 3 to about
7 g/100 kcal of a fat or lipid; [0049] ii. up to about 5 g/100 kcal of a
protein source, more preferably about 1 to about 5 g/100 kcal of a
protein source, wherein the protein source comprises from about 50% to
about 70% whey and from about 30% to about 50% casein; [0050] iii. about
1.0 to about 10.0 g/L of a prebiotic composition; [0051] iv. no greater
than about 3.90 mg/100 kcal of cholesterol, more preferably form about
2.60 to about 3.85 mg/100 kcal of cholesterol; and [0052] v. no greater
than 70 IU/100 kcal of vitamin D, more preferably from about 52 to about
67 IU of vitamin D.

Definitions

[0053] The following terms, as used herein, are defined as indicated:

[0054] "Child" and "Children" are defined as humans over the age of about
12 months to about 12 years old.

[0055] "Essential", as applied to nutrients, refers to any nutrient which
cannot be synthesized by the body in amounts sufficient for normal growth
and to maintain health and which therefore must be supplied by the diet,
while the term "conditionally essential" as applied to nutrients means
that the nutrient must be supplied by the diet under conditions when
adequate amounts of the precursor compound is unavailable to the body for
endogenous synthesis to occur.

[0056] "Infant" is a human from birth through not more than 12 months of
age, where a "newborn infant" is an infant from birth through 4 months of
age, and a "later stage infant" is an infant from 4 months of age through
1 year.

[0057] "Infant formula" applies to a composition in liquid or powdered
form that satisfies the nutrient requirements of an infant by being a
substitute for human milk. In the United States, the content of an infant
formula is dictated by the federal regulations set forth at 21 C.F.R.
§§100, 106 and 107. These regulations define macronutrient,
vitamin, mineral, and other ingredient levels in an effort to simulate
the nutritional and other properties of human breast milk.

[0058] "Full term infant" or "term infant" as used herein, means an infant
born after at least about 37 weeks gestation, and more commonly between
37 and 42 weeks gestation.

[0060] "Prebiotic" means a non-digestible food ingredient that
beneficially affects the host by selectively stimulating the growth
and/or activity of one or a limited number of bacteria in the colon that
can improve the health of the host. A "prebiotic composition" is a
composition that comprises one or more prebiotics.

[0061] "Preterm infant" is an infant born after less than about 37 weeks
gestation.

[0062] "Probiotic" means a microorganism with low or no pathogenicity that
exerts beneficial effects on the health of the host.

[0063] "Simulating," as used herein means having or taking the form or
appearance of or having or producing a symptomatic resemblance to.

Disclosure

[0064] In some embodiments, the nutritional compositions of the present
disclosure may be infant formula. In a separate embodiment, the
nutritional compositions may be a human milk fortifier, meaning it is a
composition which is added to human milk in order to enhance the
nutritional value of human milk. As a human milk fortifier, the disclosed
compositions may be in powder or liquid form.

[0065] The nutritional products of the present disclosure may provide
minimal, partial, or total nutritional support. The compositions may be
nutritional supplements or meal replacements. In some embodiments, the
compositions may be administered in conjunction with a food or
nutritional composition. In this embodiment, the compositions can either
be intermixed with the food or other nutritional compositions prior to
ingestion by the subject or can be administered to the subject either
before or after ingestion of a food or nutritional composition. The
compositions may be administered to preterm infants receiving infant
formula, breast milk, a human milk fortifier, or combinations thereof. In
one embodiment, the compositions are administered to preterm infants as
an enteral nutritional supplement.

[0066] The compositions may, but need not, be nutritionally complete. The
skilled artisan will recognize "nutritionally complete" to vary depending
on a number of factors including, but not limited to, age, clinical
condition, and dietary intake of the subject to whom the term is being
applied. The composition which is "nutritionally complete" for the
preterm infant will, by definition, provide qualitatively and
quantitatively adequate amounts of all carbohydrates, lipids, essential
fatty acids, proteins, essential amino acids, conditionally essential
amino acids, vitamins, minerals, and energy required for growth of the
preterm infant. The composition which is "nutritionally complete" for the
term infant will, by definition, provide qualitatively and quantitatively
adequate amounts of all carbohydrates, lipids, essential fatty acids,
proteins, essential amino acids, conditionally essential amino acids,
vitamins, minerals, and energy required for growth of the term infant.

[0067] The nutritional compositions may be provided in any form known in
the art, including a powder, a gel, a suspension, a paste, a solid, a
liquid, a liquid concentrate, or a ready-to-use product. In one preferred
embodiment, the nutritional compositions are infant formulae, especially
infant formulae adapted for use as sole source nutrition for a newborn
infant and a later stage infant, respectively.

[0068] In the preferred embodiments, the nutritional products disclosed
herein may be administered enterally. As used herein, "enteral" means
through or within the gastrointestinal, or digestive, tract, and "enteral
administration" includes oral feeding, intragastric feeding, transpyloric
administration, or any other introduction into the digestive tract.

[0070] Useful bovine milk protein sources include, but are not limited to,
milk protein powders, milk protein concentrates, milk protein isolates,
nonfat milk solids, nonfat milk, nonfat dry milk, whey protein, whey
protein isolates, whey protein concentrates, sweet whey, acid whey,
casein, acid casein, caseinate (e.g. sodium caseinate, sodium calcium
caseinate, calcium caseinate) and any combinations thereof, and will
include whey and casein. As noted above, the protein source of the first
nutritional composition should comprise from about 72% to about 90% whey
and from about 10% to about 28% casein; while the protein source in the
second nutritional composition should comprise from about 50% to about
70% whey and from about 30% to about 50% casein. Adjusting the
whey:casein ratio as described is also an effective way of providing for
the relative levels of other nutrients described herein.

[0071] In one embodiment, the proteins are provided as intact proteins. In
other embodiments, the proteins are provided as a combination of both
intact proteins and partially hydrolyzed proteins, with a degree of
hydrolysis of between about 4% and 10%. In still further embodiments, the
proteins comprise extensively hydrolyzed proteins. In yet another
embodiment, the protein source may be supplemented with
glutamine-containing peptides.

[0072] The nutritional compositions each contain one or more prebiotics.
Such prebiotics may be naturally-occurring, synthetic, or developed
through the genetic manipulation of organisms and/or plants, whether such
new source is now known or developed later. Prebiotics useful in the
present invention may include oligosaccharides, polysaccharides, and
other prebiotics that contain fructose, xylose, soya, galactose, glucose
and mannose. More specifically, prebiotics useful in the present
invention may include lactulose, lactosucrose, raffinose,
gluco-oligosaccharide, inulin, polydextrose, polydextrose powder,
fructo-oligosaccharide, isomalto-oligosaccharide, soybean
oligosaccharides, lactosucrose, xylo-oligosacchairde,
chito-oligosaccharide, manno-oligosaccharide, aribino-oligosaccharide,
siallyl-oligosaccharide, fuco-oligosaccharide, galacto-oligosaccharide,
and gentio-oligosaccharides. In an embodiment, the prebiotics useful in
the present disclosure are those disclosed in U.S. Pat. No. 7,572,474,
the disclosure of which is incorporated by reference herein.

[0073] In an embodiment, the total amount of prebiotics present in the
nutritional compositions may be from about 1.0 g/L to about 10.0 g/L of
the composition. As noted, the total amount of prebiotics present in the
nutritional compositions may be from about 2.0 g/L and about 8.0 g/L of
the composition. In some preferred embodiments, at least 20% of the
prebiotics comprise galacto-oligosaccharide.

[0074] In addition to galacto-oligosaccharide, the prebiotic composition
can also comprise polydextrode (PDX). If polydextrose is used as a
prebiotic, the amount of polydextrose in the nutritional composition may,
in an embodiment, be within the range of from about 1.0 g/L to about 4.0
g/L.

[0075] The amount of galacto-oligosaccharide in the nutritional
compositions may, in an embodiment, be from about 0.2 mg/100 Kcal to
about 1.0 mg/100 Kcal. In another embodiment, the amount of
galacto-oligosaccharide in the nutritional composition may be from about
0.1 mg/100 Kcal to about 0.5 mg/100 Kcal. If polydextrose is used as a
prebiotic, the amount of polydextrose in the nutritional composition may,
in an embodiment, be within the range of from about 0.1 mg/100 Kcal to
about 0.5 mg/100 Kcal.

[0076] In an embodiment of the disclosure, the nutritional compositions
may each contain one or more probiotics. The term "probiotic" means a
microorganism that exerts beneficial effects on the health of the host.
Any probiotic known in the art may be acceptable in this embodiment
provided it achieves the intended result. In a particular embodiment, the
probiotic may be selected from Lactobacillus species, Lactobacillus
rhamnosus GG, Bifidobacterium species, Bifidobacterium longum, and
Bifidobacterium animalis subsp. lactis BB-12.

[0077] If included in the compositions, the amount of the probiotic may
vary from about 104 to about 1010 colony forming units (cfu)
per kg body weight per day. In another embodiment, the amount of the
probiotic may vary from about 106 to about 109 cfu per kg body
weight per day. In yet another embodiment, the amount of the probiotic
may be at least about 106 cfu per kg body weight per day.

[0078] In an embodiment, the probiotic(s) may be viable or non-viable. As
used herein, the term "viable", refers to live microorganisms. The term
"non-viable" or "non-viable probiotic" means non-living probiotic
microorganisms, their cellular components and/or metabolites thereof.
Such non-viable probiotics may have been heat-killed or otherwise
inactivated but retain the ability to favorably influence the health of
the host. The probiotics useful herein may be naturally-occurring,
synthetic or developed through the genetic manipulation of organisms,
whether such new source is now known or later developed.

[0080] In one embodiment, the nutritional compositions are supplemented
with both DHA and ARA. In this embodiment, the weight ratio of ARA:DHA
may be from about 1:3 to about 9:1. In one embodiment, this ratio is from
about 1:2 to about 4:1.

[0081] The amount of long chain polyunsaturated fatty acids in the
nutritional compositions may vary from about 5 mg/100 kcal to about 100
mg/100 kcal, more preferably from about 10 mg/100 kcal to about 50 mg/100
kcal.

[0082] DHA and ARA supplementation may be effected using standard
techniques known in the art. For example, DHA and ARA may be added to the
formulae by replacing an equivalent amount of an oil, such as high oleic
sunflower oil, normally present in the formulae. As another example, the
oils containing DHA and ARA may be added to the formulae by replacing an
equivalent amount of the rest of the overall fat blend normally present
in the formulae without DHA and ARA.

[0083] If utilized, the source of DHA and ARA may be any source known in
the art such as marine oil, fish oil, single cell oil, egg yolk lipid,
and brain lipid. In some embodiments, the DHA and ARA are sourced from
the single cell Martek oil, DHASCO® and ARASCO®, respectively, or
variations thereof. The DHA and ARA can be in natural form, provided that
the remainder of the LCPUFA source does not result in any substantial
deleterious effect on the infant. Alternatively, the DHA and ARA can be
used in refined form.

[0084] In an embodiment of the present disclosure, sources of DHA and ARA
are single cell oils as taught in U.S. Pat. Nos. 5,374,567; 5,550,156;
and 5,397,591, the disclosures of which are incorporated herein in their
entirety by reference.

[0085] The nutritional compositions described herein can, in some
embodiments, also comprise non-human lactoferrin, non-human lactoferrin
produced by a genetically modified organism and/or human lactoferrin
produced by a genetically modified organism. Lactoferrin is generally
described as a 80 kilodalton glycoprotein having a structure of two
nearly identical lobes, both of which include iron binding sites. As
described in "Perspectives on Interactions Between Lactoferrin and
Bacteria" which appeared in the publication BIOCHEMISTRY AND CELL
BIOLOGY, pp 275-281 (2006), lactoferrin from different host species may
vary in an amino acid sequence though commonly possesses a relatively
high isoelectric point with positively charged amino acids at the end
terminal region of the internal lobe. Lactoferrin has been recognized as
having bactericidal and antimicrobial activities. Suitable lactoferrins
for use in the present disclosure include those having at least 48%
homology with the amino acid sequence AVGEQELRKCNQWSGL at the HLf
(349-364) fragment. In at least one embodiment, the lactoferrin is bovine
lactoferrin.

[0086] Surprisingly, the forms of lactoferrin included herein maintain
relevant activity even if exposed to a low pH (i.e., below about 7, and
even as low as about 4.6 or lower) and/or high temperatures (i.e., above
about 65° C., and as high as about 120° C., conditions
which would be expected to destroy or severely limit the stability or
activity of human lactoferrin or recombinant human lactoferrin. These low
pH and/or high temperature conditions can be expected during certain
processing regimen for nutritional compositions of the types described
herein, such as pasteurization. For instance, while bovine lactoferrin
has an the amino acid composition which has only about a 70% sequence
homology to that of human lactoferrin, and is stable and remains active
under conditions under which human or recombinant human lactoferrin
become unstable or inactive, bovine lactoferrin has bactericidal activity
against undesirable bacterial pathogens found in the human gut.

[0087] In yet another embodiment, the compositions may contain TGF-β.
Transforming growth factor-beta (TGF-β) is the general name for a
family of polypeptides, the members of which have multifunctional
regulatory activities. Three differentially regulated mammalian isoforms
(termed TGF-β1, TGF-β2, and TGF-β3) play important roles
in a multitude of processes in the developing embryo, infant, child and
adult. TGF-β is a 25-kDa homodimeric cytokine known to mediate
pleitropic functions both within the immune system and systemically.
TGF-β is expressed in several cell types in the intestinal mucosal
including lymphocytes, epithelial cells, macrophages, and stromal cells
as well as by T-cells, neutrophils, macrophages, epithelial cells,
fibroblasts, platelets, osteoblasts, osteoclasts and others. In addition,
TGF-β is present in human breast milk and may influence multiple
aspects of infant health and development. TGF-βs are synthesized as
large precursor proteins which consist of an amino-terminal pro-domain,
comprising a signal sequence and latency-associated complex, and a mature
carboxy-terminal subunit. Biologically active TGF-βs are homodimers
which consist of two identical, disulfide-linked mature subunits. Release
of the TGF-β homodimer from the latency-associated complex is
necessary for TGF-β to exert biological activity on target cells.
The nature of the latency-associated complex and the mechanisms
responsible for TGF-β release are key to understanding TGF-β
biological activity in vivo. In the human gut, this may be accomplished
by the action of proteolytic enzymes, pH extremes, heat, calcium, and/or
mechanical tearing.

[0088] Based on the numerous benefits provided by TGF-β, it is often
important that the growth factor is present in, or supplemented into,
various nutritional products. For example, certain protein sources in
nutritional products may provide a source of TGF-β. Alternatively,
if the nutritional product itself does not contain TGF-β, the growth
factor may be supplemented into the product. As noted above, however, the
release of TGF-β is in its inactive form. The TGF-β present in
the protein sources of nutritional products, or added to those
nutritional products, is also in its inactive form. It is then activated
in the human gut by enzymes, extremes of pH, and/or tearing.

[0089] In a further embodiment, the disclosed compositions may enhance the
bioactivity of TGF-β in the human gut from about 25% to about 75%.
In a particular embodiment, the compositions may enhance the bioactivity
of TGF-β in the human gut from about 15% to about 65%.

[0090] In certain embodiments, the level of TGF-β in the nutritional
compositions is from about 0.0150 (pg/μg) ppm to about 0.1000
(pg/μg) ppm. In another embodiment, the level of TGF-β in the
nutritional compositions is from about 0.0225 (pg/μg) ppm to about
0.0750 (pg/μg) ppm.

[0091] In a particular embodiment, the level of TGF-β in the
nutritional compositions is from about 2500 pg/mL to about 10,000 pg/mL
composition. In yet another embodiment, the level of TGF-β in the
nutritional compositions is from about 4000 pg/mL to about 6000 pg/mL.

[0092] In an embodiment, the level of TGF-β1 in the nutritional
compositions is from about 0.0001 (pg/μg) ppm to about 0.0075
(pg/μg) ppm. In another embodiment, the level of TGF-β1 in the
nutritional compositions is from about 0.0010 (pg/μg) ppm to about
0.0050 (pg/μg) ppm. In another embodiment, the level of TGF-β2 in
the nutritional compositions is from about 0.0150 (pg/μg) ppm to about
0.0750 (pg/μg) ppm. In another embodiment, the level of TGF-β2 in
the nutritional compositions is from about 0.0250 (pg/μg) ppm to about
0.0500 (pg/μg) ppm.

[0093] In certain embodiments, the ratio of TGF-β1:TGF-β2 in the
nutritional compositions is in the range of about 1:1 to about 1:20. In
certain other embodiments, the ratio of TGF-β1:TGF-β2 in the
nutritional compositions is in the range of about 1:8 to about 1:13.

[0094] In still further embodiments, the bioactivity of TGF-β within
the nutritional compositions is from about 500 nanogram equivalents (ng
Eq)/100 kcal to about 5000 ng Eq/100 kcal. In another embodiment, the
bioactivity of TGF-β within the nutritional compositions is from
about 800 ng Eq/100 kcal to about 2500 ng Eq/100 kcal.

[0095] While not wishing to be bound by this or any theory, the enhanced
TGF-β bioactivity in the human gut may be due to the composition of
the invention lowering the pH of the infant gut and allowing a greater or
faster activation of TGF-β. In addition to enhancing the activation
of TGF-β bioactivity in the human gut, it is believed that the
nutritional compositions may additionally enhance other bioactive
components in the human gut. Thus, in an embodiment, the invention is
directed to a method for enhancing the bioactivity of one or more
bioactive factors in the human gut.

[0096] In some embodiments, the bioactivity of TGF-β in a nutritional
composition is enhanced by the addition of a bioactive whey fraction. Any
bioactive whey fraction known in the art may be used in this embodiment
provided it achieves the intended result. In an embodiment, this
bioactive whey fraction may be a whey protein concentrate. In a
particular embodiment, the whey protein concentrate may be Salibra®
800, available from Glanbia Nutritionals. In a particular embodiment, the
Salibra® 800 whey protein concentrate is at least 2.5% acidified. In
another embodiment, the whey protein concentrate may be Nutri Whey 800,
available from DMV International. In yet another embodiment, the whey
protein concentrate may be Salibra-850, available from Glanbia
Nutritionals. In still another embodiment, the whey protein concentrate
may be Prolacta Lacatalis WPI90, available from Lactilus Industrie
U.S.A., Inc. In a further embodiment, the whey protein concentrate may be
supplied by MG Nutritionals.

[0097] As would be recognized by the skilled artisan, vitamins are also
considered necessary for development of an infant. Again, however, the
level of certain vitamins needed at different stages of development can
differ. For instance, with respect to vitamin D, in some embodiments the
first nutritional composition of the present disclosure should include at
least about 72 IU/100 kcal of vitamin D, more preferably from about 74 to
about 90 IU of vitamin D. The second nutritional composition should
include no greater than 70 IU/100 kcal of vitamin D, more preferably from
about 52 to about 67 IU of vitamin D.

[0098] As noted, in some embodiments, the nutritional compositions of the
present disclosure include cholesterol. Cholesterol is a steroid
metabolite found in the cell membranes and transported in the blood
plasma of animals, and is an essential structural component of mammalian
cell membranes, where it is required to establish proper membrane
permeability and fluidity. As such, cholesterol is required during
development, at levels which can vary based on the stage of development.
In certain embodiments, cholesterol is present in the first nutritional
composition at a level of at least about 3.95 mg/100 kcal and in the
second nutritional composition at a level of no greater than about 3.90
mg/100 kcal of cholesterol, more preferably from about 2.60 to about 3.85
mg/100 kcal of cholesterol. In other embodiments, cholesterol is present
in the first composition at a level of about 4.00 to about 4.90 mg/100
kcal of cholesterol, more preferably at a level of about 4.2 to about 4.7
mg/100 kcal and in the second nutritional composition at a level of from
about 2.8 to about 3.3 mg cholesterol/100 kcal.

[0099] The following examples describe various embodiments of the present
disclosure. Other embodiments within the scope of the claims herein will
be apparent to one skilled in the art from consideration of the
specification or practice of the invention as disclosed herein. It is
intended that the specification, together with the examples, be
considered to be exemplary only, with the scope and spirit of the
invention being indicated by the claims which follow the examples. In the
examples, all percentages are given on a weight basis unless otherwise
indicated.

EXAMPLE 1

[0100] This example illustrates an embodiment of the feeding regimen of
the present disclosure, including a first nutritional composition as
follows:

[0102] All references cited in this specification, including without
limitation, all papers, publications, patents, patent applications,
presentations, texts, reports, manuscripts, brochures, books, internet
postings, journal articles, periodicals, and the like, are hereby
incorporated by reference into this specification in their entireties.
The discussion of the references herein is intended merely to summarize
the assertions made by their authors and no admission is made that any
reference constitutes prior art. Applicants reserve the right to
challenge the accuracy and pertinence of the cited references.

[0103] Although preferred embodiments of the disclosure have been
described using specific terms, devices, and methods, such description is
for illustrative purposes only. The words used are words of description
rather than of limitation. It is to be understood that changes and
variations may be made by those of ordinary skill in the art without
departing from the spirit or the scope of the present disclosure, which
is set forth in the following claims. In addition, it should be
understood that aspects of the various embodiments may be interchanged
both in whole or in part. For example, while methods for the production
of a commercially sterile liquid nutritional supplement made according to
those methods have been exemplified, other uses are contemplated.
Therefore, the spirit and scope of the appended claims should not be
limited to the description of the preferred versions contained therein.